Nephrology Core Curriculum: Autosomal Dominant Cystic Kidney Disease (ADPKD and others)

Inherited Kidney Diseases Background Dominant inherited polycystic diseases ADPKD Tuberous sclerosis von Hippel-Lindau disease Recessive inherited polycystic diseases ARPKD As would be expected with recessive, onset early in life with ESRD in youth Always associated with congenital hepatic fibrosis

Tuberous Sclerosis Hereditary disease with hamartomas in multiple organ systems Autosomal dominant with high penetrance, but extreme phenotypic variability

Tuberous Sclerosis Clinical Features Hamartomas Benign tumors resulting from disordered cell migration Skin Facial angiofibromas (adenoma sebaceum) Fibrous forehead plaques Ungual fibromas Shagreen patches- lumbosacral palpable lesions Hypomelanotic macules- earliest and most common skin lesions, occurring in 90% of cases

Tuberous Sclerosis Clinical Features Hamartomas Benign tumors resulting from disordered cell migration Skin Brain Cortical tubers Associated with infantile seizures and mental retardation

Tuberous Sclerosis Clinical Features Hamartomas Benign tumors resulting from disordered cell migration Skin Brain Subependymal glial nodules Arise in the ventricles. Cause increased ICP

Tuberous Sclerosis Clinical Features Hamartomas Other organs affected: Skin Brain Retina Heart- cardiac rhabdomyomas Kidneys Liver Lungs Bone

Tuberous Sclerosis Clinical Features Hamartomas Benign tumors resulting from disordered cell migration Kidneys Present in 50% of cases #1 lesion is angiomyolipomas Benign lesion made of adipose tissue, smooth muscle cells, and arterial vessels Fat content makes them easy to diagnose by CT scan Bleeding is a risk if >4cm, esp during pregnancy Renal cysts (unrelated to angiomyolipomas) also occur in 30% of patients

Tuberous Sclerosis Diagnosis No definitive features Made by combination of major and minor features Require at least two features

Tuberous Sclerosis Management No specific therapy Consensus conference Evaluated every 1 to 3 years with renal US, CT or MRI of the brain One chest radiograph in adult women Surgical resection for CNS lesions causing hydrocephalus

Von Hippel-Lindau Disease Autosomal dominant disease with high penetrance Development of benign and malignant tumors in multiple organs Type I - NO pheos Type II- Pheos (runs in 7-20% of families)

Von-Hippel-Lindau Disease Clinical Features Potential Sites- Central nervous system, eyes, kidneys, adrenal glands, pancreas, and epididymis are commonly affected Usual lesions CNS hemangioblastomas In the cerebellum, spinal cord and brainstem. No supratentorial lesions Benign, but mass effects cause difficulties Recur after surgery

Von-Hippel-Lindau Disease Clinical Features Usual lesions Retinal hemangioblastomas In 50% of cases Multiple or bilateral Red “dots” on retina that slowly enlarge Regular ophtho eval important Laser tx

Von-Hippel-Lindau Disease Clinical Features Usual lesions Renal Cysts 50-70% of patients Carcinoma 77% of patients by 60 years old Usually multiple and bilateral #1 cause of death Inherited form of renal cancer due to the loss of a suppressor gene

Von-Hippel-Lindau Disease Clinical Features Usual lesions Pancreas Cysts in 30% of patients Likely to cause confusion with ADPKD

Von-Hippel-Lindau Disease Diagnosis Positive family history, plus a single hemangioblastoma or visceral lesion No family history, two or more hemangioblastomas or one and a visceral lesion Direct mutation analysis is now possible Distinguish from ADPKD Both with kidney cysts ADPKD with rare panc and freq hepatic VHL with rare hepatic and freq panc Suspect in any patient with kidney and pancreas cysts without liver cysts

Von-Hippel-Lindau Disease Management Regular screening program Annual physical and ophtho Annual MRI of CNS Annual abdominal imaging Either US,CT,MRI If positive family history, Periodic metanephrines screening for pheo

ADPKD Epidemiology Prevalence approximately 1:400 to 1:1000 in people of European descent 600,000 Americans with the disease More than CF, muscular dystrophy, hemophilia, Down’s syndrome and sickle cell anemia– COMBINED Frequency in Non-Europeans unknown 4% of ESRD patients Common in cats

ADPKD Genetics Two different mutations ADPKD-1 ADPKD-2– same as one, except: Milder disease Older age at diagnosis Later onset of hypertension Later onset of renal failure

ADPKD Genetics Only 1-2% of tubules affected Two-hit hypothesis– genetic abnormality not sufficient, requires an additional insult to manifest (argument for aggressive treatment of ADPKD patients) Cysts begin as focal dilatations of tubular segments Not just impermeable cul-de-sacs. They collect and store urine from more proximal nephron segments Synthesize and transport proteins, hormones, and cytokines

ADPKD Diagnosis Ultrasound Insert Australian ultrasound study Age adjusted criteria 18-29yo, at least 2 cysts 30-59yo, at least 2 cysts in each kidney >60yo, four cysts in each kidney For r/o diagnosis of ADPKD in patient at risk, no age at which 100% of gene carriers have detectable cysts US can only prove ADPKD, it cannot r/o 2 studies in families with gene linkage analysis showed no false negatives after age 30 yo (but only two families) Can’t just screen parents 10% of ADPKD patients are new mutations

ADPKD Genetics Genetic tests by linkage analysis only No direct mutation analysis Requires at least two related family members with the disease. Expensive ($1000s) Only utility is for donor screening Other reported uses include family planning decisions and prenatal diagnosis Athena diagnostics launched a molecular test based on direct mutation analysis Detects only 50% of PKD-1 and 75% of PKD-2 mutations (takes 4 weeks and $2600 by credit card)

ADPKD Signs and Symptoms Frequency Back pain and flank pain 60% of adults Hypertension 80% of adults Gross Hematuria 50% of adults Renal Concentrating defect All adults Palpable kidneys Potentially all adults Hepatomegaly 20-30% of women >50yo Proteinuria 18-68% of adults CRI Age dependent

ADPKD Signs and Symptoms Back pain Chronic- Likely the result of stretching of the renal capsule by the enlarging cysts Tylenol Physical measures- ice massage and heating packs TENS Autonomic plexus blockade Decompression of cysts Usually laproscopic. Can drain one or hundreds of cysts Immediate pain relief in 90%. Persistent relief at 3 years in 25-60% of patients Some bp improvement.

ADPKD Signs and Symptoms Hypertension Occurs well before renal insufficiency 40% by 18-24yo 54% by 24-30yo 65-80% > 30yo Hypertension correlates with renal size Mechanism clearly complex– but demonstrated to have hyperplasia of renin producing cells and increased renin levels

ADPKD Signs and Symptoms Gross hematuria Painless or associated with dull colicky pain 40-50% of patients experience at least one episode In 20% of patients it is how ADPKD is discovered Last 2-7days and cease spontaneously Can be seen on CT with contrast- high density cyst without enhancement after administration of contrast

ADPKD Signs and Symptoms Renal concentrating defect Palpable kidneys- exam is poor at estimating size Palpable hepatomegaly 20-30% of patients older than 50 UTI Must use lipophilic agents to treat Cipro, Clindamycin, Emycin, and Bactrim

ADPKD Manifestations Not just a renal process, it is a basement membrane abnormality that affects multiple sites Manifestation Frequency Renal Cysts 100% by 30 yo Nephromegaly 95% by 30 yo Decreased concentrating ability All adults Hypertension 65-80% of adults Extra-renal Liver cysts 75% by age 60yo Pancreatic cysts 9% after age 30yo Seminal vesicle and prostate cysts 60% and 11% at 40yo Arachnoid cysts 5-8% MVP 25% Intracranial Aneurysms 2-3% Abdominal Wall Hernia 45% with ESRD

ADPKD Signs and Symptoms Nephrolithiasis 20-36% Stone composition Higher uric acid than general population--- 50% Remainder CaOx Due to metabolic factors and urine stasis associated with distorted renal architecture 50% have hypocitraturia Can use lithotripsy

ADPKD Signs and Symptoms Renal Cell Cancer No increased risk Presence should raise the suspicion of a misdiagnosis Consider Von Hippel Lindau disease, esp. if familial cancers

ADPKD Urinary findings Microscopic hematuria 23% Pyuria up to 45% Dipstick Proteinuria 34-68% Nephrotic range proteinuria does not occur with ADPKD alone Only 18% with > 300mg/day proteinuria

ADPKD Extra-renal manifestations Liver cysts The most common extrarenal manifestation Arise from bile ducts Occur later than renal cysts By 60yo, 75% will have liver cysts Women > Men Multiple pregnancies puts at greater risk Despite hundreds of cysts- liver function typically remains NORMAL Can become infected- unlike renal cysts, requires drainage for clearance

ADPKD Extra-renal manifestations Cystic Other cysts Pancreas- 9% of patients >30 yo Ovaries No increase (12%) Seminal vesicles 60% No signif Prostate 11% Arachnoid cysts 8%

ADPKD Extra-renal manifestations Non-Cystic Mitral valve prolapse 25% LVH Intracranial Aneurysm Colonic divertics Increased in ADPKD ESRD patients, but not pre-ESRD Abdominal wall hernias, up to 45% Not associated with renal size or volume

ADPKD Berry Aneurysm 4 large, prospective studies screening asx subjects (High res CT,MRI, or Conventional Angiography) 5-10% of asymptomatic adults with ADPKD harbor an Intracranial aneurysm (vs. normal--???) All aneurysms found by screening were less than 8mm No change during a mean f/u of 2.5 years Annual risk of rupture for cysts <10mm is 1/2000 If >10mm or prior ruptured aneurysm 1/100-200 Risk of elective surgery Death 1-4% at one year Morbidity rate of 15% at one year

ADPKD Berry Aneurysm Sawyer’s rule of 20s 1/20 chance of having an asx aneurysm (5-10%) 1/200 chance of rupture if >10mm 1/2000 chance of rupture if <10mm 20% chance of complications with surgery 1-4% death + 15 % morbidity at one year 20% of aneurysms multiple

ADPKD Subarachnoid Hemorrhage Familial clustering of aneurysm rupture Occurs in the general population as well 5% of ADPKD, but 22% if + fhx 20-30% with have multiple aneurysms 10% who have one aneurysm rupture will have a second rupture

ADPKD Berry Aneurysm Screening recommendations Risk benefit ratio against routine screening of asx patients Screen Prior rupture Positive Family history High risk occupation- Air Line Pilots etc Prior to a surgery with hemodynamic instability associated with hypertension (KI, 1994 IC aneurysms in ADPKD) Neurologic symptoms suggestive of an aneurysm ** Trash indication** Patient’s who need screening for peace of mind

ADPKD Berry Aneurysm Questions to answer if you screen anyway How often? Does a negative screen you will never develop cysts? At what age will you develop cysts? Are you born with cysts and the remain stable for life, or do they enlarge? Serial MRAs show stability for at least 30 months No de novo aneurysms over an 8 year period Stable for 2.5 – 5 years, otherwise no data General recommendation are q5-10 years Note ADPKD patients have more CVAs than subarachnoids ADPKD patients have more hemorrhagic strokes than subarachnoids

ADPKD Pregnancy with normal renal function 235 women with 605 pregnancies ADPKD has no impact on fertility Rate of live birth unchanged 77% vs. 82% of normals Fetal complication rate- unchanged Maternal complications INCREASED (35% vs 19%) New or worsening hypertension Pre-eclampsia Edema No impact on renal function Except if FOUR or more pregnancies and hypertensive

ADPKD ESRD 50% at 60 years, 75% at 70 years at ESRD Negative prognostic factors: HTN Reviewed 1215 subjects Median renal survival 14 years longer if not hypertensive by age 35 years old LVH Male Younger age at diagnosis- -difference of ten years to ESRD between onset <30 vs >30yo 3+ pregnancies, UTIs (in men) Episodes of gross hematuria, H/o hypertension in parent If you have HTN, hematuria, and diagnosis before age 30 years old– 100% ESRD by 48 yo

ADPKD Modifier Genes ACE sub-type Sickle cell trait 2 studies show impact, 2 don’t Sickle cell trait Likely accelerates

ADPKD Treatment HTN MDRD had 200 patients with ADPKD No protective effect over a mean 2.2 years ? Disease already too far advanced Progression is slowed in animal models Use of ACE-I No evidence that hemodynamics plays an important role in progression Can perform unilateral nephrectomy without accelerating the disease process Proteinuria always less than nephrotic range However ultimate progression of disease is due to fibrosis and ACE-Is selectively block Use of amiloride Shown to block Na entry into cysts and halt cyst enlargement in animal models

ADPKD Treatment Protein restriction Cyst decompression Animal models MDRD- no protective effect on moderate or severe restriction Cyst decompression Pain management tool. No evidence for delayed disease progression Animal models Protein restriction beneficial Soy protein supplementation beneficial Flaxseed beneficial Statins beneficial Alkalinization- helps in rats, but not mice Thought is that the 2nd ammonia genesis by the kidney in order to compensate leads to tubular damage

ADPKD Counseling and Screening Newly diagnosed patients should be informed about ADPKD, it’s hereditary nature, and that children have a 50% chance of inheriting the gene Before screening, subjects should be “informed of the consequences of diagnostic screening, particularly regarding insurability.” My practice--Screening offers no benefit A negative US doesn’t r/o disease A positive US will not lead to a change in therapy, but it will make the person uninsurable and potentially unemployable Gene linkage can be performed if potential donation is considered -remember it costs approximately $2600

Acquired Cystic Kidney Disease Development of multiple, bilateral cysts in kidneys of patients with chronic renal disease due to causes other than cystic kidney disease 10-20% of pre-dialysis patients Increases with dialysis, 50% of patients on HD x 3 years with cysts Major determinant is the duration of renal insufficiency

Acquired Cystic Kidney Disease Cysts are usually less than 0.5 cm Occasionally reach 2-3cm Affect both the cortex and medulla Result of a failure to clear unknown “mytogenic and cystogenic” substances due to renal insufficiency Lesions regress with transplantation Concern is transition to cancer Men 7x more than women Some recommend screening starting at 3years with annual US Given shortened lifespan with ESRD, others refute